N-Substituted-acylamino-oxazoles as antiasthma agents

ABSTRACT

Oxazoles which are substituted in the 2,4 or 5-position with an N-substituted-acylamino group have anti-allergic activity. Methods of making such compounds, pharmaceutical compositions containing the active compounds of the invention and methods of treating asthma utilizing such compounds are provided.

This is a continuation of application Ser. No. 533,417, filed Dec. 16,1974, now abandoned.

This invention relates to heterocyclic chemical compounds and moreparticularly to certain novel oxazole derivatives which possesspharmacological activity and/or are useful as intermediates in preparingsuch active compounds. The invention also includes processes forpreparing the compounds of the invention. Furthermore the inventionincludes within its scope pharmaceutical compositions containing thepharmacologically active compounds and methods of treatment of animals,including humans, comprising administering thereto an effective dose ofthe compound or compounds or of pharmaceutical compositions comprisingthe active compound or compounds.

According to the present invention there are provided novel oxazolederivatives of the formula: ##STR1## wherein Ar represents an optionallysubstituted oxazole group, the acylamino group --NR¹ COR² being attachedat the 2,4 or 5- position thereof, R¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆alkenyl, C₂₋₆ alkoxyalkyl, C₂₋₆ carboxyalkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl, optionally substitutedphenyl-C₁₋₆ alkyl or optionally substituted phenyl-C₂₋₆ alkenyl; and R²is C₁₋₈ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₃₋₁₀ cycloalkyl, C₃₋₁₀cycloalkyl-C₁₋₆ alkyl, optionally substituted phenyl, optionallysubstituted phenyl-C₁₋₆ alkyl or optionally substituted phenyl-C₂₋₆alkenyl; or R¹ and R² together form a lactam ring having 5 to 7 ringatoms.

The oxazole nucleus may be substituted in one or both availablepositions by a group selected from formyl, carboxyl, hydroxy, C₁₋₄hydroxyalkyl, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ acyloxyalkyl or anoptionally substituted phenyl group. The available positions in theoxazole ring are the two carbon atoms not substituted by the acylaminogroup.

Compounds in which the acylamino group --NR¹ COR² is attached to the 2-position of the oxazole nucleus are preferred from the point of view ofease of preparation.

A particularly preferred class of compounds according to the presentinvention are those of formula: ##STR2## wherein R¹ is C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkoxyalkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl,optionally substituted phenyl-C₁₋₆ alkyl or optionally substitutedphenyl-C₂₋₆ alkenyl; R² is C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ alkenyl,C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, optionally substitutedphenyl, optionally substituted phenyl-C₁₋₆ alkyl or optionallysubstituted phenyl-C₃₋₆ alkenyl, or R¹ and R² together form a lactamring having 5 or 6 ring atoms, and wherein R³ and R⁴ are independentlyhydrogen, C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₈ cycloalkyl, C₃₋₆acyloxyalkyl or an optionally substituted phenyl group.

The term "C₁₋₆ alkyl" as used herein means a straight or branched chainalkyl group containing from 1 to 6 carbon atoms such as methyl, ethyl,isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-amyl, s-amyl, n-hexyl,2-ethylbutyl or 4-methylamyl.

Similarly the term "C₁₋₄ alkyl" as used herein means a straight orbranched chain alkyl group containing from 1 to 4 carbon atoms, namelymethyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, s-butyl, t-butyl."C₁₋₄ hydroxyalkyl" and "C₃₋₆ acyloxyalkyl" mean the aforementioned C₁₋₄alkyl groups substituted with an hydroxy group and acyloxy grouprespectively. "C₂₋₆ alkoxyalkyl" and "C₁₋₆ haloalkyl" mean theaforementioned C₁₋₆ alkyl groups substituted with an alkoxy group or oneor more halogen atoms, such as methoxyethyl, ethoxyethyl, ethoxybutyl,dibromoethyl, trifluoromethyl, 1-chloroethyl, 1,1-dichloroethyl,1-iodobutyl or pentafluoroethyl.

The terms "C₂₋₆ alkynyl" and "C₃₋₆ alkynyl" are used herein to indicatealicyclic hydrocarbon groups having 2 to 6 and 3 to 6 carbon atoms whichcontain a -C≡C- group. However, it should be noted that the -C≡C- groupcannot be directly adjacent to the nitrogen atom of the acylamino group.

"C₃₋₁₀ cycloalkyl" means a saturated ring having from 3 to 10 carbonatoms in the ring such as cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl, or adamantyl. "C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl" means theaforementioned saturated rings substituted with the aforementioned C₁₋₆alkyl groups at any available position.

The term "optionally substituted phenyl" as used herein means a phenylgroup unsubstituted or substituted by one or more groups which do notsubstantially alter the pharmacological activity of the compounds offormula I, such as halogen, trifluoromethyl, methyl, methoxy, or nitrogroups.

The term "carboxyalkyl" as used herein means a C₁₋₅ alkyl groupsubstituted by a carboxylic acid group. Examples of such groups arecarboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

Preferred classes of compounds falling within the scope of the oxazolesdefined in formula I or II above are those having one or more of thefollowing characteristics:

(a) R¹ is C₃₋₆ alkyl, for instance n-butyl and n-propyl,

(b) R¹ is C₃₋₄ alkenyl,

(c) R¹ is phenyl-C₁₋₂ alkyl,

(d) R² is phenyl,

(e) R² is C₁₋₄ alkyl, for instance methyl, n-propyl and i-propyl,

(f) R² is C₃₋₅ cycloalkyl,

(g) R¹ and R² taken together form a lactam ring having 5 carbon atoms,

(h) one or both of the available positions in the oxazole nucleus issubstituted by a methyl group,

(i) one or both of the available positions in the oxazole nucleus issubstituted by a hydroxymethyl group,

(j) the oxazole nucleus, not considering the acylamino group, isunsubstituted.

The present invention also provides a process for preparing the noveloxazole derivative of formula I or II which process comprises

(a) acylating,

(i) a compound of formula III:

    arNHR.sup.1                                                III

where Ar and R¹ are as defined above, or

(ii) a compound of formula Ar NH₂ with an ω-haloacyl halide andcyclising the resultant ω-haloacylamino oxazole to form a compound offormula I or II in which R¹ and R² together form a lactam ring having 5to 7 carbon atoms;

(b) alkylating a compound of formula IV: ##STR3## where Ar and R² are asdefined above.

Thus, for example, 2-(N-butyl-isobutyramido)-4-methyloxazole can beprepared by acylating 2-butylamino-4-methyloxazole or by alkylating2-isobutyramido-4-methyloxazole.

It will of course be appreciated that, when the oxazole nucleus issubstituted by hydroxyalkyl in the above compound of formula III, theresultant acylation to a compound of formula IV will also usually resultin the conversion of the hydroxyalkyl substituent to an acyloxyalkylsubstituent. The latter however may readily be selectively hydrolysedback to the desired hydroxyalkyl substituent.

The majority of the compounds of formula III and IV, are novel but someare known compounds, see for example YAKUGAKU ZASSHI 91, 425, (1971); 91436 (1971), Annalen 596, 117, (1955) and Chem. Ber. 1928 (1959).

Compounds of formula III, in which the acylamino group is at the 2-position of the oxazole nucleus, may be prepared by the condensation ofan α-hydroxy or α-acyloxy ketone or aldehyde having the followingformulae respectively: ##STR4## R³ and R⁴ being as defined above, withcyanamide or a mono-substituted cyanamide having the formula:

    R.sup.1 NH-CN                                              VII

wherein R¹ is as defined above.

Alternatively, any similar compound V or VI may be used having anappropriate leaving group instead of the acyl group.

This condensation may be carried out in the presence of an acid or abasic catalyst (the latter being much preferred) in a suitable solvent,for example aqueous dioxan. A preferred acid catalyst is aqueous HCl anda preferred basic catalyst is aqueous NaOH. The condensation andcyclisation reaction provides the intermediate 2-substituted-aminooxazole of formula III.

Cyanamide and its lower alkyl derivatives, i.e. the methyl and ethylderivatives are known (see J. Org. Chem. 38, 1325, (1973 )). Othercyanamides are novel and can be prepared by reacting a compound offormula R¹ NH₂, where R¹ is as above defined, with cyanogen bromide. Itshould be noted that, in general, cyanamides are unstable and,accordingly, should be used immediately after preparation or, if stored,should be stabilised with acetic acid or cyanogen bromide.

The acylation of the compound of formula III may be carried out with anacid halide having the formula R² CO-X wherein X is chlorine or bromineand R² is as defined above in the presence of a proton acceptor, such aspyridine or triethylamine, in an inert solvent, such as benzene.

The acylation may also be carried out by heating the amino oxazole offormula III with a suitable acid anhydride, (R² CO)₂ O, in an inertsolvent.

Those skilled in the art will immediately appreciate that a wide varietyof other acylating conditions can be used (see, for example, "TheChemistry of Amides" 1971 by A. J. Beckwith; "Survey of OrganicSynthesis", 1970 by Buehler and Pearson; "Organic Functional GroupPreparations" 1968 by Sandler and Karo; "Reagents for Organic Synthesis"1968 by Fieser and Fieser, etc.).

When it is desired that R¹ and R² should form a lactam ring, an aminooxazole, having the formula ArNH₂, is acylated with an ω-halo acylhalide and the resulting haloacylamino oxazole is cyclised in thepresence of a powerful proton acceptor such as DBN (1:5diazabicyclo[4,3,0]non-5-ene).

Compounds of formula IV can be alkylated by dissolving the amide in asuitable inert, anhydrous, polar solvent such as dimethylformamide,forming an alkali metal salt thereof with an alkali metal hydride,preferably sodium hydride, and then treating the salt with an alkylatingagent of formula R¹ X¹ where X¹ is a reactive atom such as a halogenatom or a reactive group such as an alkyl sulphate group. Alternatively,the abovementioned hydride canbe replaced by an appropriate anhydrousalkali metal carbonate such as potassium or sodium carbonate in an inertsolvent such as methyl ethyl ketone or dimethylformamide. In the lattercase, the reaction mixture is preferably heated to accomplish thealkylation. Of course, alkylating agents and alkylating reactionconditions other than those specified above can be utilised, the natureof these being readily apparent to those acquainted with the art.

It should be noted that for the preparation of compounds of formula I inwhich the acylamino group is at the 4- position of the oxazole ring,preparative difficulties may be encountered unless a compound of formulaIII is first acylated and the product IV then alkylated. In other words,for 4-acylamino oxazoles of formula I, it is highly desirable thatacylation should proceed alkylation.

It will be understood the scope of the invention extends not only to anoverall process for preparing the novel compounds of the invention asdescribed hereinbefore but also to the individual synthetic steps asherein described, and combinations of two or more of such syntheticsteps.

For the most part the intermediates of formula V and of formula VI aboveare either known compounds or may be prepared by known methods, (see,for example, Ind. Eng. Chem. 39, 55, (1949) and Org. Synth. Coll. Vol.II, p.5). A new and preferred method, however, for preparing compoundsof formula VI is that described in the specification of Roger GarrickHarrison's U.S. Pat. Application Ser. No. 533,358, now U.S. Pat. No.3,965,157 filed this even date herewith, which method involves theaddition of the aldehyde R⁴ CHO to a 2-lithio-2-R³substituted-1,3-dithiane followed by acylation and removal of thedithioacetal moiety by mercuric ion assisted hydrolysis as illustratedin the following reaction scheme: ##STR5##

As mentioned above, many intermediates of formula III and IV are novelcompounds. Such novel compounds can be represented by the generalformula VIII: ##STR6## wherein Ar is as previously defined, and Q is thegroup R¹ or --COR² provided that

(a) when Q is --COR² and the -NHQ group is attached to the 2- positionof the oxazole nucleus, R² cannot be C₂₋₆ alkyl, when

(i) one of the 4- and 5- positions of the oxazole nucleus isunsubstituted, the other being substituted by a C₁₋₄ alkyl group;

(ii) both of the 4- and 5- positions of the oxazole nucleus aresubstituted by a C₁₋₄ alkyl group; or

(iii) the oxazole nucleus is unsubstituted;

(b) when Q is --COR² and the NHQ group is attached to the 2- position ofthe oxazole nucleus, R² cannot be methyl or unsubstituted phenyl;

(c) when Q is R¹, the other two positions in the oxazole nucleus notoccupied by the --NHR¹ group cannot both be occupied by unsubstitutedphenyl groups;

(d) when Q is R¹, and the --NHR¹ group is at the 2- position of theoxazole nucleus, R¹ cannot be ethyl when the 4 and 5- positions in theoxazole ring are both substituted by methyl.

A preferred class of amine intermediates of formula VIII are those offormula (IX) : ##STR7## where R³ and R⁴ are independently hydrogen, C₁₋₄alkyl or C₁₋₄ hydroxyalkyl and wherein R¹ is C₃₋₆ alkyl.

Compounds of formula I and II have been shown to be useful in theprophylactic and therapeutic treatment of immediate hypersensitivitydiseases including asthma and in the alleviation of status asthmaticus.In certain cases the compounds have been found to be useful in diseasesin which excessive amounts of prostaglandins are released and as arespiratory stimulant. The compounds have low toxicity.

The compounds of compositions of the present invention may beadministered by various routes and for this purpose may be formulated ina variety of forms. Thus the compounds or compositions may beadministered by the oral and rectal routes, topically, parenterally,e.g. by injection and the continuous or discontinuous intra-arterialinfusion, in the form of, for example, tablets, lozenges, sub-lingualtablets, sachets, cachets, elixirs, suspensions, aerosols, ointments,for example, containing from 1 to 10% by weight of the active compoundin a suitable base, soft and hard gelatin capsules, suppositories,injection solutions and suspensions in physiologically acceptable media,and sterile packaged powders adsorbed onto a support material for makinginjection solutions. Advantageously for this purpose, compositions maybe provided in dosage unit form, preferably each dosage unit containingform 5 to 500 mg. (from 5.0 to 50 mg. in the case of parentaladministration, from 5.0 to 50 mg. in the case of inhalation and from 25to 500 mg. in the case of oral or rectal administration) of a compoundof formula I. Dosages of from 0.5 to 300 mg/kg per day, preferably 0.5to 20 mg/kg of active ingredient may be administered although it will,of course, readily be understood that the amount of the compound orcompounds of formula I or II actually to be administered will bedetermined by a physician, in the light of all the relevantcircumstances including the condition to be treated, the choice ofcompound to be administered and the choice of route of administrationand therefore the above preferred dosage range is not intended to limitthe scope of the present invention in any way.

In this specification, the expression "dosage unit form" is used asmeaning a physically discrete unit containing an individual quantity ofthe active ingredient, generally in admixture with a pharmaceuticaldiluent therefor, or otherwise in association with a pharmaceuticalcarrier, the quantity of the active ingredient being such that one ormore units are normally required for a single therapeutic administrationor that, in the case of severable units such as scored tablets, at leastone fraction such as a half or a quarter of a severable unit is requiredfor single therapeutic administration.

The formulations of the present invention normally will consist of atleast one compound of formula I mixed with a carrier, or diluted by acarrier, or enclosed or encapsulated by an ingestible carrier in theform of a capsule, sachet, cachet, paper or other container or by adisposable container such as an ampoule. A carrier or diluent may be asolid, semi-solid or liquid material, which serves as a vehicle,excipient or medium for the active therapeutic substance.

Some examples of the diluents or carriers which may be employed in thepharmaceutical compositions of the present invention are lactose,dextrose, sucrose, sorbital, mannitol, propylene glycol, liquidparaffin, white soft paraffin, kaolin, fumed silicon dioxide,microcrystalline cellulose, calcium silicate, silica,polyvinylpyrrolidine, cetostearyl alcohol, starch, modified starches,gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil oftheobroma, arachis oil, alginates, tragacanth, gelatin, syrup B.P.,methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate,methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitansesquioleate and oleyl alcohol and propellants such astrichloromonofluoromethane, dichlorodifluoromethane anddichlorotetrafluoroethane. In the case of tablets, a lubricant may beincorporated to prevent sticking and binding of the powdered ingredientsin the dies and on the punch of the tabletting machine. For such purposethere may be employed for instance aluminum, magnesium or calciumstearates, talc or mineral oil.

Examples of the novel compounds of the invention are :

2-(N-butylacetamido)-4-methyl oxazole

2(N-butylpropionamido)-4-methyl oxazole

2-(N-butylbutyramido)-4-methyl oxazole

2-(N-butylpentanamido)-4-methyl oxazole

2-(N-butylhexanamido)-4-methyl oxazole

2-(N-butylisobutyramido)-4-methyl oxazole

2-(N-butyl-2-ethylbutyramido)-4-methyl oxazole

2-(N-butylpivalamido)-4-methyl oxazole

2-(N-butylcyclopropanecarboxamido)-4-methyl oxazole

2-(N-butylcyclobutanecarboxamido)-4-methyl oxazole

2-(N-butylcclopentanecarboxamido)-4-methyl oxazole

2-(N-butylcyclohexanecarboxamido)-4-methyl oxazole

2-(N-butylcycloheptanecarboxamido)-4-methyl oxazole

2-(N-butylphenylacetamido)-4-methyl oxazole

2-(N-butylphenylpropionamido)-4-methyl oxazole

2-(N-butylbenzamido)-4-methyl oxazole

2-(N-butyl-2-chlorobenzamido)-4-methyl oxazole

2-(N-butyl-3-chlorobenzamido)-4-methyl oxazole

2-(N-butyl-4-chlorobenzamido)-4-methyl oxazole

2-(N-butyl-2-methoxybenzamido)-4-methyl oxazole

2-(N-butyl-4-methoxybenzamido)-4-methyl oxazole

2-(N-butyl-4-toluamido)-4-methyl oxazole

2-(N-butyl-3-trifluoromethylbenzamido)-4-methyl oxazole

2-(N-butyl-4-nitrobenzamido)-4-methyl oxazole

2-(N-methylacetamido)-4-methyl oxazole

2-(N-methylisobutyramido)-4-methyl oxazole

2-(N,2-diethylbutyramido)-4-methyl oxazole

2-(N-isopropylacetamido)-4-methyl oxazole

2-(N-isopropylpropionamido)-4-methyl oxazole

2-(N-isopropylbutyramido)-4-methyl oxazole

2-(N-isopropylisobutyramido)-4-methyl oxazole

2-(N-s-butylacetamido)-4-methyl oxazole

2-(N-s-butylpropionamido)-4-methyl oxazole

2-(N-s-butylbutyramido)-4-methyl oxazole

2-(N-s-butylisobutyramido)-4-methyl oxazole

2-(N-hexylacetamido)-4-methyl oxazole

2-(N-hexylisobutyramido)-4-methyl oxazole

2-(N-benzylacetamido)-4-methyl oxazole

2-(N-benzylpropionamido)-4-methyl oxazole

2-(N-benzylbutyramido)-4-methyl oxazole

2-(N-benzylisobutyramido)-4-methyl oxazole

2-(N-n-propylpentamido)-4-methyl oxazole

2-(N-[2-methoxyethyl]acetamido)-4-methyl oxazole

2-(N-[2-methoxyethyl]propionamido)-4-methyl oxazole

2-(N-[2-methoxyethyl]butyramido)-4-methyl oxazole

2-(N-[2-methoxyethyl]2-ethylbutyramido)-4-methyl oxazole

2-(N-[2-methoxyethyl]isobutyramido)-4-methyl oxazole

2-(N-allylacetamido)-4-methyl oxazole

2-(N-allylpropionamido)-4-methyl oxazole

2-(N-allylbenzamido)-4-methyl oxazole

2-(N-allylbutyramido)-4-methyl oxazole

2-(N-allyl-2-ethylbutyramido)-4-methyl oxazole

2-(N-butyldibromoacetamido)-4-methyl oxazole

2-(N-ethylacetamido)-4-methyl oxazole

2-(N-ethylbutyramido)-4-methyl oxazole

2-(N-ethylacetamido)-4,5-dimethyl oxazole

2-(N-ethylpropionamido)-4,5-dimethyl oxazole

2-(N-ethylbutyramido-4,5-dimethyl oxazole p02-(N-ethylisobutyramido)-4,5-dimethyl oxazole

2-(N-butylacetamido)-4,5-dimethyl oxazole

2-(N-butylisobutyramido)-4,5-dimethyl oxazole

2-(N-butylpropionamido)-4,5-dimethyl oxazole

2-(N-butylisobutyramido) oxazole

2-(N-butylisobutyramido)-4-isopropyl oxazole

2-(N-butylisobutyramido)-4-cyclohexyl oxazole

2-(N-butylisobutyramido)-4-phenyl oxazole

2-(N-butylisobutyramido)-4-butyl oxazole

1-(4-methyloxazol-2-yl)-2-pyrrolidone

2-(N-allylisobutyramido)-4-methyl oxazole

2-(N-cinnamylisobutyramido)-4-methyl oxazole

2-(N-crotylisobutyramido)-4-methyl oxazole

2-(N-dimethylallylisobutyramido)-4-methyl oxazole

2-(N-butylcinnamamido)-4-methyl oxazole

2-(N-butylcinnamamido)-4-methyl oxazole

2-(N-butylacrylamido)-4-methyl oxazole

2-(N-butyldimethylacrylamido)-4-methyl oxazole

2-(N-butylcrotonamido)-4-methyl oxazole

The following Examples will further illustrate the preparation of novelcompounds of the invention. Where reference is made in the followingExamples to a boiling point as being the air-bath temperature, thismeans that the compounds in question were distilled in a Kugelrohrdistillation apparatus and the temperature quoted was that of theair-bath surrounding the distillation flask during distillation of theproduct.

EXAMPLE 1 (a) n-Butylcyanamide BrCN + n-BuNH₂ → n-BuNHCN

Cyanogen bromide (94.6g., 0.88 m) in dry ether (200 c.c.) was stirredwith anhydrous sodium carbonate (200 g., 1.88m), and maintained at -20°to -10° C. during the addition of n-butylamine (88 g., 0.88 m) over 1hour. Stirring was continued for a further hour as the temperature roseto 0° C. The mixture was then filtered and evaporated to leave acolourless oil, 84 g., 96%.

A sample of the above (50 g.) was distilled at 100° C./2 mm. as acolourless mobile liquid, which rapidly polymerised unless stabilised asdescribed below.

Since alkylcyanamides tend to be unstable, one percent by weight ofcyanogen bromide was added to the cyanamide product of the reaction. Inthe presence of this stabilising agent, the n-butylcyanamide prepared bythe above reaction could be stored at room temperature with no, or onlyslight, decomposition.

When subsequent reactions were to be conducted in aqueous media, thecyanamide was prepared in a suitable water-miscible solvent (preferablyTHF) and the isolation procedure omitted.

(b) (i) 2-Butylamino-4-methyloxazole Base catalysed procedure ##STR8##

n-Butylcyanamide (13 g., 0.13 m.) and hydroxyacetone (9.7 g., 0.13 m.)in dioxan (25 cc.) were stirred during the dropwise addition of 2Nsodium hydroxide solution (70 c.c., 0.15 m.). The temperature rosespontaneously to 35° C. After the addition was complete, stirring wascontinued at room temperature for a further 2 hours.

Water (100 c.c.) was then added and the product isolated in ether.

The ether extract was washed with saturated brine, dried, and evaporatedto leave a pale yellow oil.

Distillation gave a colorless oil b.p. 80° C./0.5 mm., 14.6 g., 73%.

(ii) Acid catalysed procedure

Hydroxyacetone (2.25 g., 0.03 gave a in cold (10° C.), concentratedhydrochloric acid (2.75 c.c.) was treated with butylcyanamide (3 g.,0.03 m.). After the addition, (5 minutes) the cooling bath was removedand the temperature allowed to rise to 40° C. After a further 1 hour,the solution was poured into cold 5 N NaOH (50 c.c.) and the productisolated by extraction in ether. The extract was washed in brine, dried,and evaporated leaving a yellow oil, 3.5 g. Distillation a colourlessproduct, 2.6 g., 56%, which was identical with the product obtained inExample 1 (b) (i).

(iii) One-pot procedure

Cyanogen bromide (1457 g., 13.75 mol.) was dissolved in dry T.H.F. (7l.) and anhydrous sodium carbonate (2914 g., 27.5 mol.) was added. Themixture was cooled to below -10° C. and n-butylamine (1 kg., 13.67mol)was added slowly over 1 hour with vigorous stirring, maintaining thetemperature below -10° C. After the addition, the mixture was stirredfor a further 30 minutes at -10° C. then allowed to warm to +10° C. andfiltered.

The solids were washed with THF (500 ml.) and the combined filtrateswere diluted with water (7 l.) and 54% w/w aqueous acetol (2.8 kg.,20.41 mol.) was added. This was stirred vigorously under N₂ during theaddition of 50% aqueous sodium hydroxide (500 ml.) over 15 minutes.After the addition, the mixture was stirred for a further 11/2 hours atroom temperature and then extracted with ether (4 × 21/2 l.). Thecombined extracts were washed with water, dried over magnesium sulphateand evaporated in vacuo. The resulting oil was distilled under vacuum togive the amine 1705 g. (81%) b.p. 92-94° C./1 mm., as a pale yellow oil.

EXAMPLES 2 to 8

Using process conditions analogous to those described in Example 1 (b)(i) or (iii), the following amines were prepared:

2-methylamino-4-methyloxazole, m.p. 61-3° C.

2-butylamino-4-hydroxymethyloxazole, m.p. 57-9° C.

2-(p-chlorobenzylamino)-4-methyloxazole, m.p. 110-1° C.

5-hydroxymethyl-2-butylamino oxazole, m.p. 87-8° C.

2-benzylamino-4-methyloxazole, m.p. 112° C.

2-hexylamino-4-methyloxazole, b.p. 86-8° C./0.03 mm.

2-pentylamino-4-methyloxazole, b.p. 87° C./1.0 mm.

EXAMPLE 9 2-(N-Butylisobutyramido)-4-methyloxazole ##STR9##

2-(N-butylamino)-4-methyloxazole (106.7 g., 0.69 m.) and triethylamine(110 g., 0.77 m.) was stirred together in dry benzene (1500 c.c.) duringthe addition of isobutyrylchloride (81.0 g., 0.76 m.). The mixture wasstirred at room temperature for 15 hours and then water (1 litre) wasadded. After stirring for a further hour the organic phase wasseparated, and the aqueous phase extracted twice in ether. The combinedextract was washed successively with 2N hydrochloric acid (2 × 500c.c.), 10% sodium carbonate solution (2 × 500 c.c.), and saturated brine(2 × 500 c.c.). Evaporation of the dried organic phase gave an oil,which was distilled to give 2-(N-butylisobutyramido)-4-methyloxazole,(118 g., 80%), b.p. 75-76° C./0.15 mm., which existed as an oil at roomtemperature but crystallised on cooling to 0° C.

Found: C, 64.43; H, 9.06; N, 12.21; O, 14.02%

Calculated for C₁₂ H₂₀ N₂ O₂ : C, 64.26; H, 8.98; N, 12.49; O, 14.26%

EXAMPLE 10

2-(N-Butyl-pivalamido)-4-methyloxazole b.p. 89-91° C./0.35 mm., wasprepared in a similar manner to that of Example 2, heating the reactionunder reflux for 9 hours.

Found: C 65.25; H 9.09; N 11.51%

Calculated for C₁₃ H₂₂ N₂ O₂ : C 65.51; H 9.31; N 11.76%

EXAMPLE 11 2-(N-Butylcyclobutanecarboxamido)-4-methyloxazole

b.p. 107-8° C./0.2 mm. was prepared in a manner similar to Example 9heating the reaction mixture under reflux for 1 hour.

Found: C 66.22; H 8.30; N 11.63%

Calculated for C₁₃ H₂₀ N₂ O₂ : C 66.07; H 8.53; N 11.86

EXAMPLE 12

2-(N-Butyl-cyclopentanecarboxamido)-4-methyloxazole

b.p. 109-110° C./0.15 mm. was prepared in a manner similar to Example 9,heating the reaction mixture under reflux for 2 hours.

Found: C 66.97; H 8.65; N 11.44%

Calculated for C₁₄ H₂₂ N₂ O₂ : C 67.17: H 8.86: N 11.19%

EXAMPLE 13

2(N-Butyl-butyramido)-4-methyloxazole, b.p. 96-98° C./1 mm., wasprepared in a manner similar to Example 9.

Found: C 63.98; H 8.88; N 12.76%

Calculated for C₁₂ H₂₀ N₂ O₂ : C 64.26; H 8.98; N 12.49%

EXAMPLE 14

2-(N-Butyl-isobutyramido)-4,5-dimethyloxazole

2-Butylamino-4,5-dimethyloxazole, b.p. 79-81° C./0.1 mm. was prepared ina manner similar to that described in Example 1 using acetoin, and wasacylated as described in Example 9 to give the product, b.p. 78-79°C./0.06 mm.

Found: C 65.33; H 9.45; N 11.56%

Calculated for C₁₃ H₂₂ N₂ O₂ : C65.51; H 9.31; N 11.76%

EXAMPLE 15

2-(N-Butyl-benzamido)-4-methyloxazole, b.p. 118-120° C./0.1 mm. wassimilarly prepared as in Example 9, heating the reaction mixture underreflux for 11/2 hours.

Found: C 69.55; H 6.81; N 11.05%

Calculated for C₁₅ H₁₈ N₂ O₂ : C 69.74; H 7.02; N 10.85%

EXAMPLE 16

2-(N-Butyl-4-chlorobenzamido)-4-methyloxazole, b.p 136-138° C./0.15 mm.was similarly prepared as in Example 9 stirring the reaction mixture for24 hours at room temperature.

Found: C 61.67; H 5.61; N 9.34; Cl 12.30%

Calculated for C₁₅ H₁₇ ClN₂ O₂ : C 61.54; H 5.85; N 9.57; Cl 12.11%

EXAMPLE 17 2 -(N-Butyl-isobutyramido)-4-methyloxazole

2-N-butylamino-4-methyloxazole (15.0 gm., 0.0974 mole) and isobutyricanhydride (22 c.c.) were heated at 90° C. for fifteen minutes. Themixture was then allowed to cool and stirred for 1 hour. Excess reagentwas removed by evaporation and distillation of the resultant red oilyielded the desired compound, b.p. 75-6° C./0.15 mm. wt= 16.1 g. Yield=74%.

EXAMPLE 18 2-(N-Butyl-propionamido)-4-methyloxazole

The procedure of Example 17 was followed using 15.0 g (0.0974 m.) of2-N-butylamino-4-methyloxazole and 25 c.c. of propionic anhydride.

B.p.= 73-75° C./0.15 mm. Wt= 12.9 g. Yield= 63%

EXAMPLE 19 2-Amino-4-methyloxazole

5N Sodium hydroxide solution (125 ml.) was added dropwise to a stirredsolution of hydroxyacetone (74 g., 1mol) and cyanamide (42 g., 1 mol) inwater (110 ml.). The mixture rapidly became hot and was cooled to 20° C.and stirred at this temperature for 1 hour and then extracted with ether(3 × 250 ml.). The ether extract was washed with sodium chloridesolution, dried over sodium sulphate and then evaporated under vacuum.The residue was distilled under vacuum to give the product 76.8 g. (78%)b.p. 66-67° C./0.5 mm. n_(d) ²³ 1.495.

EXAMPLE 20 2-(2-Ethylbutryamido)-4-methyloxazole -Ethylbutyramido)-

A stirred solution of 2-amino-4-methyloxazole prepared as described inExample 19 (8.8 g., 0.089 mol) and 2-ethylbutyric anhydride (19.0 g.,0.089 mol) in toluene (50 ml) was heated under reflux for 2 hours. Thecooled solution was washed with sodium carbonate solution, then withsodium chloride solution, dried over sodium sulphate and evaporated. Thesolid residue was recrystallised from ethyl acetate-petroleum spiritgiving white crystals. 10.1 g. (58%) m.p. 106° C.

EXAMPLES 21 - 34

By appropriate modification of the starting materials and reactionconditions described in Example 20, the following amides were prepared:

2-isobutyramido-4-methyloxazole, m.p. 10°-111° C.

2-trifluoroacetamido-4-methyloxazole, m.p. 173°-5° C.

2-butyramido-4-methyloxazole, m.p. 99° C.

2-butyramido-4-ethyloxazole, m.p. 85° C.

2-isobutyramido-5-ethyloxazole, m.p. 118° C.

2-acetamido-4-ethyloxazole, m.p. 96°-8° C.

2-trifluoroacetamido-4-ethyloxazole, m.p. 143° C.

2-isobutyramido-5-methyloxazole, m.p. 109° C.

2-hexanamido-4-methyloxazole, m.p. 66° C.

2-valeramido-4-methyloxazole, m.p. 84°-5° C.

2-butyramido-4,5-dimethyloxazole, m.p. 82°-3° C.

2-propionamido-4,5-dimethyloxazole, m.p. 119°-120° C.

2-propionamido-4-methyloxazole, m.p. 113°-4° C.

EXAMPLE 35 2-(N-Ethyl-2-ethylbutyramido)-4-methyloxazole

Sodium hydride (2.8 g. of a 50% dispersion in oil, 0.058 mol) was addedin small portions to a stirred solution of2-(2-ethylbutyramido)-4-methyloxazole (8.0 g., 0.041 mol) indimethylformamide (100 ml.) at -5° to 0° C. The mixture was stirred for2 hours at room temperature and then ethyl iodide (4.7 ml. 0.058 mol)was added. The mixture was stirred for a further 2 hours at roomtemperature and then poured onto ice-water (250 ml.) and extracted withether (3 × 100 ml.). The extract was washed with dilute hydrochloricacid, then with sodium chloride solution, dried over sodium sulphate andevaporated. The residue was distilled under vacuum to give the product4.7 g. (51%) b.p. 71-72° C/0.3 mm.

Found: C 64.10; H 8.69; N 12.35%

Expect for C₁₂ H₂₀ N₂ O₂ : C 64.26; H 8.98; N 12.49%

EXAMPLE 36 2-(4-Chlorobutyramido)-4-methyloxazole

2-Amino-4-methyloxazole (5.0 g., 0.0509 mol) was dissolved in drybenzene (100 mls.) and triethylamine (5.70 g., 0.0563 mol) was added.The mixture was stirred vigorously at room temperature and4-chlorobutyrylchloride (7.88 g., 0.0558 mol) in dry benzene (50 mls.)was added rapidly. After the addition the mixture was heated underreflux for 2 hours. The mixture was then cooled and filtered. Thefiltrate was placed in a separating funnel and washed successively withwater (1 × 100 mls.), 10% Na₂ CO₃ (2 × 100 mls.) and water (3 × 100mls.). The organic layer was dried over magnesium sulphate andevaporated under vacuum. The product was recrystallised from ethylacetate/hexane. Wt. = 2.47 g.m.p. 98° C. (Yield = 23.92%).

EXAMPLE 37 1-(4-methyloxazol-2-yl)-2-pyrrolidone

2(4-Chlorobutyramido)-4-methyloxazole (2.20 g., 0.018 mol) prepared asdescribed in Example 36 was dissolved with stirring under nitrogen indry benzene (350 mls.) and 1:5-diazobicyclo[4,3,0]non-5-ene (1.47 g.,0.0118 mol) in dry benzene (50 mls.) was added with stirring over 10minutes. The mixture was stirred at room temperature, wrapped in foilovernight. The organic layer was washed with water (3 × 100 mls.) driedover magnesium sulphate and evaporated under vacuum. The product wasrecrystallised from ethyl acetate/hexane. WT.= 0.75 g. m.p. 116° C.(Yield = 41.57%).

EXAMPLE 38 2-(N-Butylamino)-4-phenyloxazole

The procedure as described in Example 1 was followed using phenacylalcohol and butylcyanamide. A colourless oil was obtained afterdistillation of the product.

Wt. Wt.= 5.0 g., 47% Yield. b.p. 134° C/0.1 mm., which crystallised onstanding. The analytical sample which separated as needles from petrol(40-60° C.) had m.p. 52-53° C.

Found: C 71.9; H 7.2; N 13.2%

C₁₃ H₁₆ N₂ O requires: C 72.2; H 7.45; N 12.95%

EXAMPLE 39 2-(N-Butyl-isobutyramido)-4-phenyloxazole

2-(N-butylamino)-4-phenyloxazole was acylated with isobutyryl chlorideas described in Example 9. An almost colourless oil was obtained ondistillation. WT.= 4.9 g., b.p. 140° C. (air-bath temperature)/1 mm.,80%.

C₁₇ H₂₂ N₂ O₂ requires: C 71.3; H 7.7; N 9.8%

Found: C 71.4; H 7.5; N 9.6%

EXAMPLE 40 2-(N-Butylamino)-4-isopropyloxazole

The procedure of Example 1 was followed using the keto acetate, (CH₃)₂##STR10## and butylcyanamide.

Distillation gave a colourless product (3.5 g., 68%) b.p. 130°C.(airbath temperature)/0.3 mm.

C₁₀ H₁₈ N₂ O requires: C 66.0; H 10.0; N 15.4%

Found: C 65.8%; H 10.2; N 15.1%

EXAMPLE 41 2-(N-Butyl-isobutyramido)-4-isopropyloxazole

2-(N-Butylamino)-4-ispropyloxazole was acylated with isobutyryl chlorideas described in Example 9.

Distillation gave a colorless oil (4.5 g., 68%), b.p. (air-bath) 145°C./0.7 mm.

C₁₄ H₂₄ N₂ O₂ requires: C 66.7; H 9.6; N 11.1%

Found: C 66.7; H 10.0; N 10.9%

EXAMPLE 42 2-(N-Butylacetamido)-4-methyloxazole

The procedure of Example 17 was followed using 15.0g. (0.0974 m) of2-butylamido-4-methyl oxazole and 25 c.c. of acetic anhydride.

B.p.= 58-60° C./0.1 mm. wt.= 14.4 g. yield= 75.4%.

EXAMPLE 43

2-(N-Benzylisobutyramido)-4-methyloxazole, was suitably prepared as inExample 9.

B.p.= 124° C./0.6 mm wt.= 7.2. g.

EXAMPLE 44

2-(N-[3-chlorobenzyl]isobutyramido)-4-methyloxazole

2-iso Butyramido-4-methyloxazole (11.1 g., 0.066 mol) prepared in amanner similar to that described in Example 20, was dissolved in drydimethylformamide. Solid potassium carbonate (10.47 g., 0.076 mol) and3-chlorobenzyl bromide (15.6 g., 0.076 mol) were added and the stirredmixture was heated at 70° C. for 2 hours, cooled and poured into coldwater. The solution was extracted with ether and the extract was driedover magnesium sulphate and evaporated. The residue was distilled togive the product, 12.3 g., b.p. 115-120° C./0.08 mm.

EXAMPLES 45 - 171

Using analogous procedures to those utilised in Examples 1 to 44, thefollowing compounds were prepared:

2-(N-butylpentanimido)-4-methyloxazole, b.p. 88- 91° C./0.2 mm.

2-(N-butylhexanamido)-4-methyloxazole, b.p. 102° C./0.3 mm.

2-(N-butyl-2-ethylbutyramido)-4-methyloxazole, b.p. 127° C./2.5 mm.

2-(N-butylcyclopropanecarboxamido)-4-methyloxazole, b.p. 97- 100° C./0.5mm.

2-(N-butylcyclohexanecarboxamido)-4-methyloxazole, m.p. 46.5- 48.5° C.

2-(n-butylcycloheptanecarboxamido)-4-methyloxazole, b.p. 138- 141° C./1mm.

2(N-butylphenylacetamido)-4-methyloxazole, b.p. 126- 130° C./0.2 mm.

2-(N-butyl-3-phenylpropionamido)-4-methyloxazole, b.p. 137- 138° C./0.2mm.

2-(N-butyl-2-chlorobenzamido)-4-methyloxazole, b.p. 130- 131° C./0.2 mm.

2-(N-butyl-3-chlorobenzamido)-4-methyloxazole, b.p. 145- 147° C./0.4 mm.

2-(N-butyl-2-methoxybenzamido)-4-methyloxazole, b.p. 158- 160° C./0.8mm.

2-(N-butyl-4-methoxybenazmido)-4-methyloxazole, b.p. 162- 163° C./1.0mm.

2-(N-butyl-4-toluamido)-4-methyloxazole, b.p. 139- 140° C./0.7 mm.

2-(N-butyl-3-trifluoromethylbenzamido)-4-methyloxazole, b.p. 114- 115°C./0.3 mm.

2-(N-butyl-4-nitrobenzamido)-4-methyloxazole, b.p. 178- 180° C./1.0 mm.

2-(N-methylacetamido)-4-methyloxazole, m.p. 27- 29° C.

2-(N-methylisobutyramido)-4-methyloxazole, b.p. 49- 50° C./0.35 mm.

2-(N-ethylacetamido)-4-methyloxazole, b.p. 50- 51° C./0.05 mm.

2-(N-ethylbutyramido)-4-methyloxazole, b.p. 63- 64° C./0.1 mm.

2-(N-isopropylacetamido)-4-methyloxazole, b.p. 75° C./3.0 mm.

2-(N-isopropylpropionamido)-4-methyloxazole, b.p. 65° C./0.5 mm.

2-(N-isopropylbutyramido)-4-methyloxazole, b.p. 69° C./0.35 mm.

2-(N-isopropylisobutyramido)-4-methyloxazole, b.p. 60- 62° C./0.4 mm.

2-(N-s-butylacetamido)-4-methyloxazole, b.p. 64° C./0.6 mm.2-(N-s-butylpropionamido)-4-methyloxazole, b.p. 76° C./0.4 mm.

2-(N-s-butylbutyramido)-4-methyloxazole, b.p. 75- 76° C./0.5 mm.

2-(N-s-butylisobutyramido)- 4-methyloxazole, b.p. 82° C./0.8 mm.

2(N-hexylacetamido)-4-methyloxazole, b.p. 96- 92° C./0.08 mm.

2-(N-hexyisobutyramido)-4-methyloxazole, b.p. 106- 109° C./1.0 mm.

2-(N-benzylacetamido)-4-methyloxazole, b.p. 119- 120° C./0.3 mm.

2-(N-benzylpropionamido)-4-methyloxazole, b.p. 132- 133° C./0.3 mm.

2-(N-benzylbutyramido)-4-methyloxazole, b.p. 128° C./0.15 mm.

2-(N-propylpentanamido)-4-methyloxazole, b.p. 83 84° C./0.2 mm.

2-(N-[2-methoxyethyl]acetamido)-4-methyloxazole, b.p. 84° C./0.6 mm.

2-(N-[2-methoxyethyl]propionamido)-4-methyloxazole, b.p. 88° C./0.4 mm.

2(N-2-methoxyethyl]butyramido)-4-methyloxazole, b.p. 96° C./0.4 mm.

2-(N-[2-methoxyethyl]-2-ethylbutyramido)-4-methyloxazole, b.p. 98°C./C./0.4 mm.

2-(N-[2-methoxyethyl]isobutyramido)-4-methyloxazole, b.p. 84- 85°C./0.05 mm.

2-(N-[2-methoxyethyl]isobutyramido)-4-methyloxazole, b.p. 84- 85°C./0.05 mm.

2-(N-allylacetamido)-4-methyloxazole, b.p. 67° C./ 0.8 mm.

2-(N-allylpropionamido)-4-methyloxazole, b.p. 75° C./0.8 mm.

2-(N-allylbenzamido)-4-methyloxazole, b.p. 119° C./0.7 mm.

2-(N-allylbutyramido)-4-methyloxazole, b.p. 76° C./0.6 mm.

2-N-allyl-2-ethylbutyramido)-4-methyloxazole, b.p. 83° C./0.65 mm.

2-(N-ethylacetamido)-4,5-dimethyloxazole, b.p. 61- 62° C./0.3 mm.

2-(N-ethylpropionamido)-4,5-dimethyloxazole, b.p. 68- 69° C./0.3 mm.

2-(N-ethylpropinamido)-4,5-dimethyloxazole, b.p. 68- 69° C./0.3 mm.

2-(N-ethylbutyramido)-4,5-dimethyloxazole, b.p. 68- 70° C./0.25 mm.

2-(N-ethylisobutyramido)-4,5-dimethyloxazole, b.p. 63- 65° C./0.25 mm.

2-(N-butylacetamido)-4,5-dimethyloxazole, b.p. 89- 91° C./1.0 mm.

2-(N-butylpropinoamido)-4,5-dimethyloxazole, b.p. 86- 88° C./0.4 mm.

2-(N-butylisobutyramido)oxazole, b.p. 120° C./0.5 mm.*

2-(N-butylisobutyrmido)-4-cyclohexyloxazole, b.p. 165° C./0.4 mm.*

2-(N-butylisobutyramido)-4-butyloxazole, b.p. 140° C./0.05 mm.*

2-(N-butylacetamido)-5-acetoxymethyloxazole, b.p. 170° C./0.5 mm.*

5-isobutyroxymethyl-2-(N-butylisobutyramido)oxazole, b.p. 180° C./0.5mm.*

5-cyclohexyl-2(N-butylisobutyramido)-oxazole, b.p. 170° C./0.5 mm.

2-(N-cyclopentylvaleramido)-4-methyloxazole, b.p. 102°-104° C./0.2 mm.

2-(N-2'-methoxyethylcyclopentanecarboxamido)-4-methyloxazole, b.p. 117°C./1.0 mm.

2-(N-2'-phenethylpropionamido)-4-methyloxazole, b.p. 126° C./0.6 mm.

2-(N-2'-phenethylacetamido)-4-methyloxazole, b.p. 122° C./0.5 mm.

2-(N-allylisobutyramido)-4-methyloxazole, b.p. 68° C./0.5 mm.

2-(N-β-phenethylbutyramido)-4-methyloxazole, b.p. 133° C./0.7 mm.

2-(N-β-phenethylisobutyramido)-4-metnyloxazole, b.p. 128° C./0.65 mm.

4-isobutyroxymethyl-2-(N-butylisobutyramido)oxazole, b.p. 180° C./0.5mm.*

2-(N-butylbenzamido)-4,5-dimethyloxazole, b.p. 125°-128° C./0.5 mm.

2-(N-butylvaleramido)-4,5-dimethyloxazole, b.p. 102°-105° C./0.5 mm.

2-(N-butylcyclobutanecarboxamido)-4,5-dimethyloxazole, b.p. 105°-107°C./0.5 mm.

2-(N-butylbutyramido)-4,5-dimethyloxazole, b.p. 95-98° C./0.5 mm.

2-(N-butyl-3-nitrobenzamido)-4-methyloxazole, b.p. 152°-155° C./0.2 mm.

2-(N-[2-methylbutyl]-butyramido)-4-methyloxazole, b.p. 87° C./0.5 mm.

2-(N-[2-methylbutyl]-propionamido)-4-methyloxazole, b.p. 82°-83° C./0.5mm.

2-(N-(2-methylbutyl]-isobutyramido)-4-methyloxazole, b.p. 83° C./0.5 mm.

2-(N-pentylbenzamido)-4-methyloxazole, b.p. 130° C./0.7 mm.

2-(N-cyclohexylpropionamido)-4-methyloxazole, b.p. 101° C./0.5 mm.

2-(N-ethylhexanamido)-4-methyloxazole, b.p. 94°-96° C./0.7 mm.

2-(N-butylcyclohexanecarboxamido)-4,5-dimethyloxazole, b.p. 122°-126°C./0.5 mm.

2-(N-butylcyclopentanecarboxamido)-4,5-dimethyloxazole, b.p. 112°-116°C./0.5 mm.

2-(N-cyclohexylbutyramido)-4-methyloxazole, b.p. 118° C./0.7 mm.

2-(N-butyl-3,4-dichlorobenzamido)-4-methyloxazole, b.p. 162°-165° C./1.0mm.

2-(N-pentylbutyramido)-4-methyloxazole, b.p. 98° C./0.8 mm.

2-(N-benzylbenzamido)-4-methyloxazole, m.p. 62° C.

2-(n-benzylvaleramido)-4-methyloxazole, b.p. 134° C./0.7 mm.

4,5-dimethyl-2-(N-methylacetamido)oxazole, m.p. 40°-42° C.

2-(n-butyl-1-adamantanecarboxamido)-4-methyloxazole, b.p. 160° C./0.3mm.

2-(N-ethyl-2-ethylbutyramido)-4-methyloxazole, b.p. 71°-2° C./0.3 mm.

2-(N-butyl-4-fluorobenzamido)-4-methyloxazole, b.p. 120°-2° C./0.3 mm.

4-methyl-2-(N-propyl hexanamido)oxazole, b.p. 96°-8° C./0.4 mm.

4-methyl-2-[N-(1-ethylpropyl)-butanamido]oxazole, b.p. 58°-60° C./0.5mm.

4-methyl-2-[N-(1-ethylpropyl)-pentamido]oxazole, b.p. 91° C./0.5 mm.

2-(N-pentyl propanamido)-4-methyloxazole, b.p. 68° C./0.05 mm.

2-(N-pentyl isobutyramido)-4-methyloxazole, b.p. 86°-7° C./0.4 mm.

2-(N-butyl isobutyramido)-4-ethyloxazole, b.p. 140° C./0.5 mm.*

2-(N-isopropyl pentanamido)-4-methyloxazole, b.p. 77° C./0.3 mm.

2-(N-butyl dichloroacetamido)-4-methyloxazole, b.p. 112°-4° C./0.8 mm.

2-(N-p-chlorobenzyl isobutyramido)-4-methyloxazole, b.p. 136° C./0.7 mm.

2-(N-hexyl propanamido)-4-methyloxazole, b.p. 106°-8° C./1.0 mm.

2-(N-butyl chloroacetamido)-4-methyloxazole, b.p. 96°-8° C./1.0 mm.

2-(N-butyl isobutyramido)-4-methyl-5-hydroxyoxazole

(-) 2-(N-but-2-yl butanamido)-4-methyloxazole, b.p. 86°-9° C./1.2 mm.

(+) 2-(N-but-2-yl butanamido)-4-methyloxazole, b.p. 85°-8° C./1.5 mm.

2-(N-butyl-N-isobutyramido)-4-hydroxymethyloxazole, b.p. 185° C./0.3mm.*

2-(N-benzyl hexanamido)-4-methyloxazole, b.p. 144° C./0.6 mm.

2-(N-butyl-4-chlorobutanamido)-4-methyloxazole, b.p. 124°-8° C./1.2 mm.

2-(N-prop-1-yn-3-yl-isobutyramido)-4-methyloxazole, b.p. 87° C./0.5 mm.

2-(N-butyl isobutyramido)-4-p-chlorophenyloxazole, b.p. 200° C./0.5 mm.*

2-(N-butyl-isobutyramido)-5-methyloxazole, b.p. 100° C./0.1 mm.*

1-(4-methyl oxazol-2-yl)-2-oxo-hexahydro-1H-azepine, b.p. 130° C./0.1mm.*

2-(N-cyclopentyl isobutyramido)-4-methyloxazole, m.p. 73° C.

D(-) 2-(n-butyl-2-methylbutanamido)-4-methyloxazole, b.p. 88°-92° C./0.6mm.

L(+) 2-(n-butyl-2-methylbutanamido)-4-methyloxazole, b.p. 88°-91° C./0.6mm.

2-(N-butyl-2-methylbutanamido)-4-methyloxazole, b.p. 82°-5° C./0.2 mm.

2(N-butyl acetamido)-4-carbethoxyoxazole, b.p. 170° C./0.1 mm.*

2-N-(butylisobutyramido)-5-phenyloxazole, b.p. 190° C./0.2 mm.*

2-[N-(3-carbethoxypropyl)isobutyramido]-4-methyloxazole, b.p. 122°-5°C./0.4 mm.

2-(N-cinnamyl isobutyramido)-4-methyloxazole, b.p. 152°-156° C./1.0 mm.

2-[N-(4-methylbenzyl)isobutyramido]-4-methyloxazole, b.p. 120°-4° C./0.3mm.

2-[N-(3-methylbenzyl)isobutyramido]-4-methyloxazole, b.p. 118°-122°C./0.3 mm.

2-(N-butyl-heptanamido)-4-methyloxazole, b.p. 106°-8° C./0.05 mm.

2-(N-butyl cyclopentylacetamido)-4-methyloxazole, b.p. 124°-6° C./0.8mm.

2-(N-cyclohexylmethyl isobutanamido)-4-methyloxazole, b.p. 122°-4°C./0.8 mm.

2-[N-(4-methoxybenzyl)isobutyramido]-4-methyloxazole, b.p. 145°-8°C./0.4 mm.

2-(N-butylcinnamamido)-4-methyloxazole, b.p. 200° C./0.2 mm.

2-[N-(3-carboxypropyl)octanamido]-4-methyloxazole, b.p. 200° C./0.2 mm.

2-[N-(3-carbethoxypropylpentanamido]-4-methyloxazole, b.p. 142°-5°C./0.6 mm.

2-[N-(3-chloropropyl)pentanamido]-4-methyloxazole, b.p. 118°-122° C./0.7mm.

2-[N-(3-chloropropyl)isobutyramido]-4-methyloxazole, b.p. 99°-102°C./0.5 mm.

2-(N-butylbut-2-enamido)-4-methyloxazole, b.p. 150° C./0.02 mm.

2-(N-butylisobutyramido)-5-ethyloxazole, b.p. 70°-72° C./0.2 mm.

2-(N-butyltrifluoroacetamido)-4-methyloxazole, b.p. 67°-69° C./0.8 mm.

Microanalysis (C,H,N) for each of the compounds listed in Examples 45 -171 was (within the limits of experimental error) equal to the expectedtheoretical result. In addition, infra-red, ultra-violet and protonmagnetic resonance spectra were consistent with the assigned structures.

EXAMPLE 172 5-Hydroxy-2(N-butylisobutyramido)-4-methyloxazole

4-methyl-2(N-butylisobutyramido)oxazole (15 g., 0.067 m.) in drymethylene chloride (100 c.c.) was cooled to 0° C. during the addition ofm-chloroperbenzoic acid (16 g., 0.023 m.) over 1 hour. The mixture wasthen stirred at room temperature for 40 hours. The precipitatedm-chlorobenzoic acid was then filtered off and the filtrate evaporatedto dryness. The residue was taken in ether (100 c.c.) and stirred with5% aqueous sodium sulphite solution for1 hour. The organic phase wasthen separated and washed successively with aqueous sodium carbonate(×2) and water, and then dried and evaporated to give a brown oil, 13.9g.

A portion of the above product (10 g.) was dissolved in ether and washedwith 1N NaOH (2 × 25 c.c.). The cooled aqueous phase was acidified with2N hydrochloric acid and extracted into ether. The washed (aqueous Na₂CO₃ and water) organic phase was dried and evaporated to give a yellowoil (4.05 g.). The product was then chromatographed on a column ofalumina (Brockman grade II, 200 g.). Elution with ethyl acetate removedless polar impurities, whilst the product (2.5g.) was eluted with 5%MeOH/ethylacetate.

C₁₂ H₂₀ N₂ O₃ requires: C 60.1; H 8.4; N 11.7% Found: C 59.8; H 8.4; N11.7%

The product was further characterised by conversion into its methylether with silver oxide and methyl iodide in DMF.

C₁₃ H₂₂ N₂ O₃ requires: C 61.5; H 8.7; N 11.0% Found: C 61.6%; H 8.8; N11.3%

EXAMPLE 173 (a) 2-isobutyramido-5-methyloxazole

2-Amino-5-methyloxazole (3.30 g., 0.0336 mol) prepared by the method ofBerichte 95 2419 (1962) was added to dry benzene (40 ml.) and isobutyricanhydride (5.90 g., 0.0372 mol) was added. The mixture was heated underreflux for 3 hours. Methanol (5 ml.) and triethylamine (5 drops) werethen added cautiously and the mixture was heated for a further 30minutes. The mixture was then cooled and washed with water (2 × 20mls.), 10% aqueous sodium carbonate (3 × 25 mls.) and water (3 × 20mls.). The organic phase was then dried over magnesium sulphate andevaporated under reduced pressure. The solid was then recrystallisedfrom hexane Yield = 1.44 g. (25.5%) m.p. 109°-109.5° C.

Analysis Th. for C₈ H₁₂ N₂ O₂

Th. C 57.13% H 7.19% N 16.66% O 19.02% Fd. C 57.40% H 7.20% N 16.52% O19.07%

(b) 2-(N-butyl-isobutyramido)-5-methyloxazole ##STR11##

2-isobutyramido-5-methyloxazole (2.10 g., 0.0124 mol), prepared asabove, was dissolved in dry dimethylformamide (10 mls.) and cooled tobelow 5° C. To this was added sodium hydride (0.70 g., 0.0145 mol.)portionwise, keeping the temperature below 5° C. After the addition, themixture was stirred for a further 30 minutes at 5° C. and then allowedto warm to room temperature. The iodobutane (5.0 g., 0.0271 mol.) wasadded. The mixture was stirred overnight, the solvent was evaporatedunder reduced pressure and the residue was partitioned between water (50mls.) and ether (50 mls.). The organic phase was then washed with 2N HCl(2× 25 mls.), water (1× 25 mls.), 10% aqueous sodium carbonate (3× 25mls.) and water (3× 25 mls.). The organic phase was then dried overmagnesium sulphate and evaporated under reduced pressure. The residuewas distilled from a Kugelrohr, air bath temperature 100° C./0.1 mm.Yield= 1.74 g. (62%).

Analysis for C₁₂ H₂₀ N₂ O₂

Th. C 64.26% H 8.98% N 12.49% Fd. C 64.08% H 8.73% N 12.21%

EXAMPLE 174 4-Formyl-2-(N-Butylisobutyramido)-oxazole ##STR12##

The alcohol (5 g., 0.0206 m.) was added to a stirred solution ofchromium trioxide (14.8 g.) and pyridine (23.6 g.) in methylene chloride(600 c.c.). The mixture was stirred at room temperature for 15 minutes,and then filtered and evaporated. Ether was added to the residue and themixture was again filtered and evaporated. The resulting pale brown oilwas distilled at 150° C. (air-bath)/0.2 mm., as a colourless oil 3.1 g.,63%.

C₁₂ H₁₈ N₂ O₃ requires: C 60.6; H 7.6; N 11.8% Found: C 60.4; H 7.9; N11.55%

EXAMPLE 175 4-Carboxy-2-(N-butylisobutyramido)-oxazole ##STR13## Thealdehyde (3 g., 0.0126 m.) was stirred in THF/water (9:1) (80 c.c.) withAg (II)O (15 g.) for 15 hours. The solution was then filtered and theresidue washed in methanol.

THF and methanol were then removed in vacuo, and the residue wasdissolved in ether, and stirred for 1 hour with 2N HCl.

Separation of the ether layer, drying and evaporation gave the crudeacid (1.5 g.), which was distilled at 180° C. (air-bath)/0.25 mm. togive a crystalline solid, 1.1 g., 34%. The acid was recrystallised fromhexane as fine white needles m.p. 70°- 72° C.

C₁₂ H₁₈ N₂ O₄ requires C 56.75; H 7.1; N 11.0% Found: C 56.8; H 7.2; N10.8%

EXAMPLE 176 5-(N-butyl-trifluoroacetamido)-2-methyloxazole

2-Acetamido-N-butylacetamide (18.70 g, 0.1085 mol) made by the method inJ. A. C. S. 71 2899(1949), was dissolved in dry chloroform (200 ml.) andtrifluoroacetic anhydride (45.06 g., 0.2170 mol) was added dropwise withstirring under nitrogen. Heat was evolved. The mixture was stirred for 4hours under nitrogen and then solid anhydrous sodium carbonate (50.0 g.,0.4717 mole) was added portionwise with stirring. After 30 minutes,solid was filtered off and was washed with dry chloroform (2× 25 ml.).The combined filtrates were evaporated under reduced pressure. The oilwas then distilled under vacuum to give the desired product 11.37 g.(42%) b.p. 51°-2° C./0.1 mm.

The product was a colourless oil.

Required for C₁₀ H₁₃ N₂ O₂ F₃ C 48.00% H 5.2% N 11.20% F 22.78% Found C47.72% H 5.08% N 10.93% F 22.62%

EXAMPLE 177 (a) 2-Benzamido-N-benzyl-N-methylpropanamide

N-Benzoylalanine cyanomethyl ester (29.80 g., 0.1283 mol), prepared bythe method described in Bull. Soc. Chem. Fr. 3127 (1973), was dissolvedin ethyl acetate (300 mls.) and benzylmethylamine (31.10 g., 0.2566 mol)was added. The reaction mixture was stirred at room temperature for 7days and then the mixture was washed with 2N HCl (6× 50 mls.) water (1×50 mls.), 10% aqueous sodium carbonate (2× 50 mls.), and finally water(3× 50 mls.). The organic phase was dried over magnesium sulphate andevaporated under reduced pressure to give a dark oil. This waschromatographed on silica using chloroform to give a partially purifiedmaterial. This was then distilled from a Kugelrohr air-bath apparatus at230° C., pressure 0.01 mm. to give a pale yellow oil.

(b) 5-(N-benzylmethylamino)-4-methyl-2-phenyloxazole

2-Benzamido-N-benzyl-N-methylpropanamide (8.0 g., 0.0269 mol.), wasdissolved in dry chloroform (40 ml.) and trifluoroacetic anhydride (17.0g., 0.0809 mol.) was added dropwise with stirring under nitrogen. Themixture was stirred for 4 hours, then sufficient anhydrous sodiumcarbonate was added portionwise to neutralise the acid formed. The solidwas filtered off and washed with dry chloroform (2× 10 ml.). Thecombined filtrates were evaporated under reduced pressure to give abrown oil, which was extracted with warm pentane. The pentane solutionwas evaporated to give a yellow oil 6.20 g. (82.5% IR and NMR confirmthe structure.

(c) 5-(N-methyl acetamido)-4-methyl-2-phenylaoxazole

10% Palladium/charcoal catalyst (0.30 g.) was weighed out and aceticanhydride (30 mls.) was cautiously added under nitrogen.

5-(N-Benzylmethylamino)-4-methyl-2-phenyloxazole (3.0 g., 0.0167 mole)was added and the mixture was hydrogenated at room temperature andatmospheric pressure for 24 hours. The catalyst was filtered off and themixture was evaporated under reduced pressure. A sample was purified onpreparative thin layer chormatography.

Mass spectra showed the mass ion to be 230 (correct value) and thefragmentation pattern was consistent with the correct product.

EXAMPLE 178 (a) 2-Acetamido-N-benzyl-N-methylacetamide

N-Acetylglycine cyanomethyl ester (96.0 g., 0.6148 mol.), prepared bythe method described in Roczniki Chem. 34 1488 (1960), was dissolved inwarm ethyl acetate (1 L) and benzylmethylamine (225.0 g. 1.8566 mol.)added with stirring under nitrogen. The mixture was heated under refluxfor 2 hours. The solvent was evaporated under reduced pressure. Theexcess amine was distilled off under vacuum and the residue was thendistilled to give a pale yellow viscous oil 90.56 g. (67%) b.p.160°-165° C./0.05 mm.

(b) 5-(N-benzylmethylamino)-2-methyloxazole

2-Acetamido-N-benzyl-N-methylacetamide (10.0 g., 0.0453 mol.) wasstirred under nitrogen at room temperature and phosphoryl chloride (33mls.) was added rapidly. The mixture was stirred for 4 hours, then theexcess reagent was evaporated under reduced pressure. The dark oil wasthen dissolved in a small amount of chloroform and added slowly to astirred mixture of sodium carbonate in ice, ensuring that the mixtureremained alkaline. The organic phase was then separated and the aqueousphase was extracted with more chloroform. The combined extracts wereevaporated to give a dark oil. The dark oil was purified bychromatography on alumina and then distilled. b.p. 130° C./0.1 mm.*

(c) 5-(N-methyl acetamido)-2-methyloxazole

Using similar reaction conditions to those described in Example 177 (c),the title compound was prepared. Confirmation of its structure wasobtained by mass spectra evidence.

EXAMPLE 179 (a) t-Butyl-4-(2-phenyloxazolyl)-carbamate ##STR14##

2-Phenyloxazole-4-carboxylic acid (9.45 g., 0.05 m.), prepared by themethod of Cornforth and Cookson [J. Chem. Soc. 1086, (1962)],dimethoxyethane (25 c.c), triethylamine (5.05 g., 0.05 m.) and t-butanol(10 c.c), were mixed and cooled at 0° C. in an atmosphere of nitrogen.Diphenylphosphonic azide (10.75 c.c., 0.05 m.) was then added slowly.When the addition was complete, the temperature was raised to 80° C.when evolution of nitrogen was apparent. The temperature was maintainedat 80°-90° C. for 21/2 hours. The solution was then cooled, diluted withwater and extracted in ethyl acetate. The organic extract was washedwith aqueous sodium carbonate solution and water, and then dried (Na₂SO₄) and evaporated. The resulting brown oil was eluted through a shortcolumn of neutral alumina with ether. Evaporation of the eluate gavewhite crystals, 5.3 g., 44% m.p. 121-125° C.

C₁₄ H₁₆ N₂ O₃ requires: C 64.7; H 6.2; N 10.8% Found: C 64.7; H 6.4; N10.7%

(b) 2-Phenyl-4-isobutyramido-oxazole(XV) ##STR15##

(XIII) (5 g., 0.019 m.) in dry DMF (20 c.c) was cooled at 0° C. undernitrogen. Sodium hydride (1 g., of a 50% suspension) was then addedslowly. After a further 30 minutes at 0° C., isobutyryl chloride (2.5g., 1.8 c.c. 0.0235 m.) was added dropwise. Stirring was continued for 1hour as the temperature rose to 20° C. Water was then added, and theproduct isolated in ether. Evaporation of the dried organic extract gavean oil, 5.8 g., which crystallised on standing. A small samplecrystallised from petrol (40°- 60° C.) as white flakes, m.p. 72°-80° C.

The crude carbamate (XIV) (5.5 g., 0.166 m.) was refluxed in methylethyl ketone (25 c.c.) containing anhydrous lithium iodide (2.5 g.) for15 hours. Solvent was then removed in vacuo, and the residual oilpartitioned in ether and water. The aqueous phase was acidified to pH2,and then the ether phase was separated, dried, and evaporated. Theresulting brown oil was passed through a silica column with chloroform.Evaporation of the eluate gave a crystalline solid, which separated fromether/petrol (40°-60° C.) as colourless needles, 1.2 g., m.p. 142°-143°C.

C₁₃ H₁₄ N₂ O₂ requires: C 67.9; H 6.1; N 12.2% Found: C 67.9; H 6.1; N12.3%

(c) 2-Phenyl-4(N-butylisobutyramido)oxazole ##STR16##

(XV) (1.1 g., 0.0048 m.) was cooled at 0° C. in dry DMF (20 c.c.) andNaH (0.25 g., of 50% dispersion) was added. After 30 minutes at 0° C.,butyl iodide (1 g., 0.0052 m.) was added. The temperature rose to 20° C.over a period of 3 hours. Water was then added and the product wasisolated in ether. The pale brown extract was passed through a shortalumina column with ether, and the colourless eluate was evaporated todryness. The residue was distilled at 180° C. (air-bath)/0.2 mm. to giveXVI as a colourless oil, 1.2 g. 88%.

Examples 180- 197

Using process conditions analogous to those described in Example 1 (b)the following amines were prepared:

2-propylamino-4-methyloxazole, b.p. 65°-67° C./0.3 mm,

2-t-butylamino-4-methyloxazole, b.p. 44°-48° C./0.3 mm.

2-cyclopentylamino-4-methyloxazole, m.p. 67° C.

2-s-butylamino-4-methyloxazole, b.p. 68°-70° C./1.0 mm.

(+) 2-s-butylamino-4-methyloxazole b.p. 71°-72° C./1.4 mm.

(-) 2-s-butylamino-4-methyloxazole, b.p. 68°-70° C./1.2 mm.

2(4-methoxybenzylamino)4-methyloxazole, m.p. 94° C.

2-cyclohexylmethylamino-4-methyloxazole, b.p. 110°-113° C./0.8 mm.

2-allylamino-4-methyloxazole, b.p. 62°-64° C./0.4 mm.

2-isopropylamino-4-methyloxazole, b.p. 66° C./0.1 mm.

2(2-methoxyethylamino)4-methyloxazole, b.p. 72°-73° C./0.7 mm.

2(2-phenylethylamino) 4-methyloxazole, b.p. 134° C./0.7 mm.

2(2-methyl-butylamino) 4-methyloxazole, b.p. 101° C./2.5 mm.

2-cyclohexylamino-4-methyloxazole, b.p. 112° C./2.0 mm.

2-pentylamino-4-methyloxazole, b.p. 87° C./1.0 mm.

2-(1-ethylpropylamino)- 4-methyloxazole, b.p. 65°-66° C./0.2 mm.

2-ethylamino-4-methyloxazole, b.p. 85°-90° C./8 mm.

2-ethylamino-4,5-dimethyloxazole, b.p. 57°-59° C./0.2 mm.

EXAMPLES 197 to 199

By appropriate modification of the starting materials and reactionconditions described in Example 20, the following amides were prepared:

2-phenylacetamido-4-methyloxazole, m.p. 177° C.

2-octanamido-4-methyloxazole, m.p. 61°-63° C.

EXAMPLE 200 2-[N-(3-Carboxypropyl)-isobutyramido]-4-methyloxazole

A solution of 2[N-(3-carbethoxypropyl)-isobutyramido]-4-methyloxazole(9.9 g., 0.035 mol.) prepared in a manner similar to that described inExample 44 was dissolved in ethanol (100 ml.) and N NaOH solution (35ml.) and the solution was stirred for 20 hours at ambient temperature.The solution was evaporated and the residue was dissolved in water,washed with ether, acidified and extracted with ether. The extract wasdried and evaporated and the residue was recrystallised from benzene--petrol to give the product 5.1 g., m.p. 81°- 82° C.

EXAMPLE 201

Similarly prepared was:

2-[N-(3-carboxypropyl)-octanamido]-4-methyloxazole, b.p. 200° C./0.2 mm.

The following Examples 202- 210 illustrate pharmaceutical formulationscontaining the active compound 2-(N-butylisobutyramido)-4-methyloxazole.

EXAMPLE 202

Soft gelatin capsules were prepared using the following ingredients;

    ______________________________________                                                          Quantity (mg/capsule)                                       ______________________________________                                        Active compound     25                                                        Butylated hydroxyanisole B.P.                                                                     0.02                                                      Fractionated Coconut Oil B.P.C.                                                                   75                                                                            100.02                                                    ______________________________________                                    

The above ingredients were mixed and filled into soft gelatin capsules,the main shell components of which were gelatin and glycerine.

EXAMPLE 203

The procedure of Example 202 was repeated except that an identicalquantity of propyl gallate was used in place of the butylatedhydroxyanisole as antioxidant.

EXAMPLE 204

Hard gelatin capsules were prepared using the following ingredients

    ______________________________________                                                         Quantity (mg/capsule)                                        ______________________________________                                        Active compound    25                                                         Silicon dioxide (fumed)                                                                          25                                                         Lactose            50                                                         Butylated hydroxyanisole B.P.                                                                    0.02                                                       ______________________________________                                    

The butylated hydroxyanisole was dissolved in the active ingredient andthe solution so formed adsorbed onto the silicon dioxide (fumed). Thelactose was then added and the whole mixed. Finally, the mixture wasfilled into hard gelatin capsules.

Alternatively, the solution of butylated hydroxyanisole and activecompound can be diluted with an inert solvent, the solution slurriedonto the silicon dioxide (fumed) and the inert solvent evaporated off.The lactose is then mixed in and the mixture filled into the hardgelatin capsules.

EXAMPLE 205

An injectible solution was prepared containing the following components:

    ______________________________________                                        Active ingredient       25 mg.                                                Cremophor EL            25 mg.                                                Ethanol                 25 mg.                                                Water                   25 mg.                                                Butylated hydroxyanisole B.P.                                                                         0.02 mg.                                              ______________________________________                                    

The butylated hydroxyanisole was dissolved in the active ingredient andethanol, the water and Cremophor EL added and the solution sterilised byfiltration through a bacteria proof filter into sterile containers.

EXAMPLE 206

An ointment was made up from the following ingredients

    ______________________________________                                        Active compound       1% by weight                                            Butylated hydroxyanisole B.P.                                                                       0.02% by weight                                         White soft paraffin   q.s. 100%                                               ______________________________________                                    

The hydroxyanisole was dissolved in the melted paraffin and the activecompound then added in, and the mixture allowed to cool.

EXAMPLE 207

A topical cream containing 0.5% of the compound is prepared as follows:

    ______________________________________                                                          grams                                                       ______________________________________                                        Active Compound     0.5                                                       Cetomacrogol 1000   2.8                                                       Cetostearyl alcohol 11.2                                                      Liquid Paraffin     8.0                                                       Butylated hydroxyanisole B.P.                                                                     0.02                                                      Distilled water     to 100.0                                                  ______________________________________                                    

The compound is mixed with the hydroxyanisole and suspended in theliquid paraffin. The cetostearyl alcohol is added and the mixture heatedto 70° C. with stirring. The cetomacrogol 1000 is dissolved in 60 g. ofwater heated to 70° C. The cetostearyl alcohol and liquid paraffinactive compound mixture are then poured into the aqueous cetomacrogol1000 solution with stirring and the stirring is continued until thecream is cold. The cream is then made up to weight with water and passedthrough a stainless steel colloid mill set at a gap of 15/1000 inch.

EXAMPLE 208

Suppositories containing 25 and 50 mg. of the compound are prepared asfollows:

    ______________________________________                                        Active compound   2.5 g.                                                      Henkel base      97.5 g.                                                      ______________________________________                                    

The active compound is mixed with the Henkel base which had beenpreviously melted using the minimum amount of heat possible. The mixtureis then poured into suppository moulds of a nominal capacity of 1 g. or2 g. as desired, to produced suppositories each containing 25 mg. or 50mg. of the active compound.

EXAMPLE 209

An aerosol was prepared containing the following ingredients:

    ______________________________________                                                        Quantity per ml.                                              ______________________________________                                        Active compound    10.00 mg.                                                  Propylene glycol   10.00 mg.                                                  Dichlorotetrafluoroethane                                                                       562.50 mg.                                                  (Propellant 114)                                                              Dichlorodifluoromethane                                                                         829.50 mg.                                                  (Propellant 12)                                                               ______________________________________                                    

The active compound is mixed with the propylene glycol and the mix addedto the propellant 114, the mixture cooled to -15 to -20° C. andtransferred to a filling device. At the same time a mixture ofpropellants 114 and 12, previously cooled to -15° to -20° C. is fed intoa second filling device. A metered amount of propellant from the secondfilling device is introduced into a stainless steel container, followedby the required amount of material from the first filling device. Thevalve units are then fitted and sealed to the container. These valveunits may be equipped with metering device so that approximately 0.15mg. of the active compound is released by a single actuation of thevalve.

EXAMPLE 210

Tablets were prepared using the following components

    ______________________________________                                        Active compound     10.00 mg.                                                 Microcrystalline Cellulose                                                                        250.00 mg.                                                Sodium Carboxymethyl Starch                                                                       25.00 mg.                                                 Magnesium Stearate   3.00 mg.                                                 Butylated Hydroxyanisole B.P.                                                                      0.002 mg.                                                ______________________________________                                    

The hydroxyanisole was dissolved in the active compound, the solutionadsorbed onto the microcrystalline cellulose. This was mixed with thesodium carboxymethylcellulose and then the magnesium stearate was mixedin. Finally, the mixture was compressed to form tablets.

In the foregoing Examples 202 to 210, the liquid active compound usedmay, in accordance with the invention, be replaced wholly or in part byother liquid active compounds of formula I or II. If the active compoundis a solid, appropriate modification will of course have to be made.

We claim:
 1. An oxazole selected from the group consistingof:2-(N-butyl-isobutyramido)-4-methyloxazole,2-(N-butyl-hexanamido)-4-methyloxazole,2-(N-butyl-pivalamido)-4-methyloxazole,2-(N-butyl-isobutyramido)-4,5-dimethyloxazole,2-(N-butyl-butyramido)-4-methyloxazole,2-(N-hexyl-isobutyramido)-4-methyloxazole,2-(N-butyl-iso-butyramido)-oxazole,2-(N-butyl-pentanamido)-4-methyloxazole,2-(N-propyl-pentanamido)-4-methyloxazole,2-(N-butyl-phenylacetamido)-4-methyloxazole,2-(N-cyclopentyl-pentanamido)-4-methyloxazole,2-(N-butyl-pentanamido)-4,5-dimethyloxazole,2-(N-butyl-butyramido)-4,5-dimethyloxazole,2-(N-cyclohexyl-butyramido)-4-methyloxazole,2-(N-pentyl-butyramido)-4-methyloxazole,2-(N-propyl-hexanamido)-4-methyloxazole,2-(N-pentyl-isobutyramido)-4-methyloxazole,2-(N-butyl-isobutyramido-4-ethyloxazole,2-(N-butyl-isobutyramido)-4-hydroxymethyloxazole,2-(N-butyl-isobutyramido)-5-methyloxazole,2-(N-cyclopentyl-isobutyramido)-4-methyloxazole,L(+)-2-(n-butyl-2-methylbutyramido)-4-methyloxazole,2-(N-butyl-2-methylbutyramido)-4-methyloxazole,2-[N-(4-methoxybenzyl)-isobutyramido]-4-methyloxazole,2-(N-butyl-cinnamamido)-4-methyloxazole,2-(N-butyl-but-2-enamido)-4-methyloxazole, and2-(N-butyl-isobutyramido)-5-ethyloxazole.
 2. An N-substituted acylaminooxazole selected from the group consistingof2-(N-butyl-acetamido)-4-methyloxazole,2-(N-sec-butyl-butyramido)-4-methyloxazole,2-(N-benzyl-propionamido)-4-methyloxazole,2-N-butyl-propionamido)-4-methyloxazole,2-(N-butyl-cyclobutylcarboxamido)-4-methyloxazole,2-(N-butyl-cyclohexanecarboxamido)-4-methyloxazole,2-(N-butyl-cyclopentane carboxamido)-4-methyloxazole,2-(N-butyl-benzamido)-4-methyloxazole,2-[N-butyl-(4-chlorobenzamido)]4-methyloxazole,2-(N-butyl-acetamido)-5-acetoxymethyloxazole,2-(N-butyl-cycloheptylcarboxamido)-4-methyloxazole,2-(N-2-propenyl-propionamido)-4-methyloxazole,2-(N-butyl-cyclopropylcarboxamido)-4-methyloxazole,2-(N-butyl-isobutyramido)-5-cyclohexyloxazole,2-(N-butyl-1-adamantylcarboxamido)-4-methyloxazole,2-(N-allyl-butyramido)-4-methyloxazole,2-(N-butyl-3-trifluoromethylbenzamido)-4-methyloxazole,2-(N-butyl-3-chlorobenzamido)-4-methyloxazole,2-[N-(2-phenylethyl)-propionamido]-4-methyloxazole2-(N-butyl-isobutyramido)-4-isobutyryloxy methyloxazole,2-[N-(2-methylbutyl)-butyramido]-4-methyloxazole,2-[N-(2-methylbutyl)-propionamido]-4-methyloxazole,2-[N-(2-methylbutyl)-isobutyramido]-4-methyloxazole,2-(N-butyl-4-fluorobenzamido)-4-methyloxazole,2-(N-pentyl-propionamido)-4-methyloxazole,2-(N-hexyl-propionamido)-4-methyloxazole,2-(N-butyl-chloroacetamido)-4-methyloxazole,2-(N-butyl-isobutyramido)-4-methyl-5-hydroxyoxazole,1-2-(N-sec-butyl-butyramido)-4-methyloxazole,d-2-(N-sec-butyl-butyramido)-4-methyloxazole,2-(N-butyl-isobutyramido)-4-formyloxazole,2-(N-butyl-4-chlorobutyramido)-4-methyloxazole,2-(N-2-propynyl-isobutyramido)-4-methyloxazole,2-[N-(3-methylbenzyl)-isobutyramido]-4-methyloxazole,5-(N-butyl-trifluoroacetamido)-2-methyloxazole,2-[N-(3-carboxypropyl)-octanamido]-4-methyloxazole,2-[N-(3-chloropropyl)-pentanamido]-4-methyloxazole,2-[N-(3-chloropropyl)-isobutyramido]-4-methyloxazole, and5-(N-methyl-acetamido)-4-methyl-2-phenyloxazole.
 3. A pharmaceuticalformulation useful for treating asthma in animals comprising an amountsufficient to treat asthma of an oxazole of claim 1 in association witha pharmaceutically acceptable carrier therefor.
 4. A pharmaceuticalformulation useful for treating asthma in animals comprising an amountsufficient to treat such asthma of an oxazole of claim 2 in associationwith a pharmaceutically acceptable carrier therefor.
 5. A method oftreating an animal suffering from asthma which comprises administeringto such animal an amount effective for treating asthma of an oxazole ofclaim
 1. 6. A method of treating an animal suffering from asthma whichcomprises administering to such animal an amount effective for treatingasthma of an oxazole of claim
 2. 7. An oxazole according to the formula##STR17##
 8. A pharmaceutical formulation useful for treating asthma inanimals comprising a therapeutically effective amount of2-(N-butyl-isobutyramido)-4-methyloxazole in association with apharmaceutically acceptable carrier therefor.
 9. A method of treating ananimal suffering from asthma which comprises administering to suchanimal an amount effective for treating asthma of2-(N-butyl-isobutyramido)-4-methyloxazole.